Dengue is the second most important infectious tropical disease after malaria with approximately one-half of the world's population living in areas where there is a risk of epidemic transmission. There are estimated to be 50-100 million cases of dengue fever every year resulting in 500,000 patients being hospitalized for hemorrhagic dengue fever and resulting in approximately 25,000 deaths. Dengue fever virus infections are endemic in more than 100 tropical countries and hemorrhagic dengue fever has been documented in 60 of these countries (Gubler, 2002, TRENDS in Microbiology, 10: 100-103; Monath, 1994, Proc. Natl. Acad. Sci., 91: 2395-2400).
Dengue fevers are caused by four viruses of the flavivirus genus which are of similar serological type but differ antigenically (Gübler et al., 1988, in: Epidemiology of arthropod-borne viral disease. Monath TPM, editor, Boca Raton (Fla.): CRC Press: 223-60; Kautner et al., 1997, J. of Pediatrics, 131: 516-524; Rigau-Pérez et al., 1998, Lancet, 352: 971-977; Vaughn et al., 1997, J. Infect. Dis., 176: 322-30). “Dengue fever viruses” or “dengue viruses” are positive single-strand RNA viruses belonging to the Flavivirus genus of the family of flaviviridae. The genome in RNA comprises a 5′ type I end but lacks a 3′ poly-A tail. The organization of the genome comprises the following elements: a 5′ non-coding region (NCR), a region encoding structural proteins (capsid (C), pre-membrane/membrane (prM/M), envelope (E)) and a region encoding non-structural proteins (NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5) and a 3′ NCR. The viral genomic RNA is associated with the capsid proteins to form a nucleocapsid. Typical of flaviviruses, the dengue viral genome encodes an uninterrupted coding region which is translated into a single polyprotein which is post-translationally processed.
Dengue viruses are maintained within a cycle involving mammals and the Aedes mosquito. Infection in a mammal is initiated by injection of the dengue virus during the blood meal of an infected Aedes mosquito whereby the dengue virus is primarily deposited in the extravascular tissues. The incubation period of the virus after a mosquito bite is approximately 4 days (from 3 to 14 days).
The first category of mammalian cells to be infected after inoculation of the mammalian subject are the dendritic cells, which then migrate to the lymphatic ganglia (Wu et al., 2000, Nature Med., 7: 816-820). In addition to dendritic cells, monocytes and macrophages are among the first targets of dengue virus. After initial replication in the skin and lymphatic ganglia, the dengue virus appears in the blood in the course of the acute febrile stage, generally for 3 to 5 days.
Infection with one serotype of dengue may produce a spectrum of clinical disease from non-specific viral syndrome to severe fatal hemorrhagic disease. Routine laboratory diagnosis of dengue fever is based on isolation of the virus and/or the detection of antibodies specific to dengue fever virus. Primary infection may be asymptomatic or may result in dengue fever. Dengue fever is characterized by a two-phase fever, headaches, pains in various parts of the body, prostration, eruptions and lymphadenopathy (Kautner et al., 1997, J. of Pediatrics, 131: 516-524; Rigau-Pérez et al., 1998, Lancet, 352: 971-977). The viremic period is of the same length as the febrile period (Vaughn et al., 1997, J. Infect. Dis., 176: 322-30). Cure of dengue fever is complete after 7 to 10 days, but prolonged asthenia is normal. Reduced leukocyte and platelet numbers frequently occur.
Dengue haemorrhagic fever (DHF) is a potentially deadly complication of dengue virus infection. DHF is characterized by a high fever and symptoms of dengue fever, but with extreme lethargy and drowsiness. Increased vascular permeability and abnormal homeostasis can lead to a decrease in blood volume, hypotension, and in severe cases, hypovolemic shock and internal bleeding. Two factors appear to play a major role in the occurrence of hemorrhagic dengue fever—rapid viral replication with a high level of viremia (the severity of the disease being associated with the level of viremia; Vaughn et al., 2000, J. Inf. Dis., 181: 2-9) and a major inflammatory response with the release of high levels of inflammatory mediators (Rothman and Ennis, 1999, Virology, 257: 1-6). The mortality rate for hemorrhagic dengue fever can reach 10% without treatment, but is ≤1% in most centers with experience of treatment (WHO Technical Guide, 1986. Dengue hemorrhagic fever: diagnosis, treatment and control, p. 1-2. World Health Organization, Geneva, Switzerland).
Dengue shock syndrome (DSS) is usually a progression of DHF and is frequently fatal. DSS results from generalized vasculitis leading to plasma leakage into the extravascular space. DSS is characterized by rapid and poor volume pulse, hypotension, cold extremities, and restlessness.
The four serotypes of dengue virus possess approximately 60-80% sequence homology. Infection with one dengue serotype provides durable homologous immunity but limited heterologous immunity. (Sabin, 1952, Am. J. Trop. Med. Hyg., 1: 30-50). Consequently, an individual may subsequently become infected with a different serotype. A second infection arising from a different serotype of dengue fever is, in theory, a risk factor for the development DHF. The majority of patients that exhibit DHF have been previously exposed to at least one of the four serotypes of dengue viruses. However, DHF is multifactorial—factors include the strain of virus involved and the age, immune status and genetic predisposition of the patient. It is thought that upon homologous re-infection, antibodies specific to the serotype bind to the surface proteins and prevent the virus from binding to target cells. However, upon re-infection by a heterologous dengue serotype, the heterologous virus will activate the immune system to attack as if it was the first serotype. These antibodies to the prior serotype bind to but do not inactivate the virus. The immune response attracts numerous macrophages which the heterologous serotype then infects. It is hypothesized that the antibodies generated by a previous dengue serotype infection can result in symptoms of enhanced severity when the individual is subsequently infected by a different dengue serotype. Consequently, it is desirable to immunize an individual against all four serotypes of dengue.
There is no specific treatment against dengue fever. Treatment for dengue fever is symptomatic, with bed rest, control of the fever and pain through antipyretics and analgesics, and adequate drinking. The treatment of hemorrhagic dengue fever requires balancing of liquid losses, replacement of coagulation factors and the infusion of heparin.
One population particularly susceptible to the effects of dengue virus infection are children. The effects of dengue virus infection are more severe in children. Although, the availability of multiple pediatric vaccines has alleviated the threat of multiple diseases to the pediatric population, the recommended administration of these vaccines has created an increasingly complex and crowded schedule of vaccinations. Current protocols for the administration of dengue vaccines anticipate the need for multiple vaccinations to ensure complete protection against all serotypes. The addition of such a dengue vaccination schedule to the already crowded childhood vaccination schedule raises issues of compliance with the recommended pediatric vaccination schedule, particularly in those areas of the world where regular availability of healthcare is difficult to obtain. Unfortunately, these same areas are where the threat of dengue fever is particularly acute. Consequently, there is a desire to combine multiple vaccines by co-administration to enhance compliance with the recommended vaccination schedule.
There has been some success in minimizing the frequency of vaccination by combining multiple vaccinations into a single dosage form. However, there is the potential for incompatibility among the different agents in a single dosage form. Additionally, the administration of multiple vaccines at a single time also creates issues for effective vaccination. Whenever a multivalent vaccine is administered (or multiple vaccines are co-administered) in combination, each individual antigen of the combination induces an immunological response. It is possible to inhibit the immune system's ability to adequately respond to all of the antigens administered and not provide a durable protective response to one or more of the antigens.
The present invention addresses the foregoing needs by providing methods and compositions to enable concomitant mumps, measles and rubella vaccination with dengue vaccination against dengue serotypes 1, 2, 3, and 4.